There is still a need in the art for cytotoxic agents for use in cancer therapy. Antimicrotubule drugs are a major category of anticancer agents (Rowinsky, E. K., and Tolcher, A. W. Antimicrotubule agents. In: V. T. Devita, Jr., S. Hellman, and S. A. Rosenberg (eds.), Cancer Principles and Practice, Ed. 6, pp. 431–452. Philadelphia: Lippincott Williams and Wilkins, 2001). Antimicrotubule drugs work by interfering with the function of cellular microtubules, particularly the mitotic spindle. The disruption of normal spindle function leads to apoptotic cell death.
Many tumors are inherently resistant (e.g., colon tumors) or become resistant after multiple cycles of treatment, at least in part due to the expression of drug transporters located in cancer cell membranes that pump the drugs out of cells and thereby decrease their efficacy (Gottesman, M. M. Mechanisms of cancer drug resistance. Annu. Rev. Med., 53: 615–627, 2002). The best known of these transporters is P-glycoprotein. Accordingly, there is a need for new agents with taxane-like effects on microtubule polymerization that are not substrates of P-glycoprotein or other such pumps and that therefore will overcome this cause of taxane resistance in patients.
Accordingly, there is ongoing research for new clinical candidates. There is also a search for new and improved methods of preparation of those selected clinical candidates.
The preparation and use of 5-phenylpyrimidines having the following general formula
as fungicides are disclosed in WO02/074753 A2.
The preparation and use of 4-amino-2-(pyrin-2-yl)pyrimidines having the following general formula
as microbicidal active substances are disclosed in US 2003/0092718 A1.
Published patent application US2005-0075357A1 describes 5-arylpyrimidines as anticancer agents. The reference discloses 6-chloro-5-{2,6-difluoro-4-[3-(methylamino)proxy]phenyl}-2-pyrazin-2-yl-N-[(1S)-2,2,2-trifluoro-1-methylethyl]pyrimidin-4-amine and its hydrochloride. The hydrochloride has been found to have the disadvantage of being very hygroscopic.
The present invention overcomes the disadvantage of the hygroscopicity of the hydrochloride salt.